When Antioxidants Are

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CANCER data strongly suggest that an increase in basal antioxidant capacity can contribute to cancer development. So why are mutations in KEAP1 and NRF2 relatively rare in cancers? When antioxidants DeNicola and colleagues’ insightful study3 now shows that the Keap1–Nrf2 pathway in mouse cells can also be activated by means are bad other than mutations in Keap1 or Nrf2. They find that the K-Ras oncogene can regulate Reactive oxygen species (ROS) get a bad press, as evidenced by the notable trend Nrf2 transcription through a Mek–Erk–Jun in the use of dietary and cosmetic antioxidants. New work suggests, however, signalling pathway, and cause a correspond- that ROS might have a role in mitigating certain cancers. See Letter p.106 ing reduction in ROS in primary fibroblasts. This effect depends on levels of oncogene activation: expression of K-Ras at ‘endogenous’ RUSHIKA M. PERERA to extrinsic or intrinsic cellular stress, how- levels, akin to those observed as tumour cells & NABEEL BARDEESY ever, NRF2 is stabilized, entering the nucleus develop from normal cells, reduces ROS levels, to activate cytoprotective genes6. Indeed, the whereas huge increases in K-Ras expres- igh levels of reactive oxygen species KEAP1–NRF2 pathway regulates more than sion induce cellular stress and increase ROS (ROS) have been considered to pro- 100 protective genes, including components levels. Importantly, the authors present evi- mote cancer1,2. Yet the levels of Nrf2 — of an antioxidant system that can balance high dence in mice that an antioxidant program is Hthe transcription factor that mainly regulates ROS levels7. Notably, mutations that cause induced in the early stages of K-Ras-driven physiological antioxidant pathways — is also NRF2 stabilization, and so confer permanent pancreatic-cancer development. Moreover, increased in some cancers. Writing on page protection against oxidative stress, have been they report that transcriptional activation of 106 of this issue, DeNicola et al.3 provide evi- detected in subsets of human lung, head- Nrf2 could be part of the tumorigenic activity dence in mice that several oncogenes actively and-neck, and gall-bladder cancers7. These of other oncogenes such as Braf and c-Myc, and induce transcription of Nrf2, promoting therefore contribute to the development a ROS detoxification program that is of other malignancies such as lung cancer. required for tumour initiation. Thus, this study highlights two impor- Activated oncogene Tumour cells can bypass normal tant points: a stress-response program is responses to cellular stress by switching turned on early in tumour development; on programs driven by oncogenic muta- and oncogene activity is coupled with the tions and changes in metabolism that transcriptional induction of Nrf2 (Fig. 1). allow sustained growth even in envir ↑ Nrf2 It is therefore possible that a larger onments where nutrients and oxygen spectrum of cancers utilize this non- are scarce. This highly deregu- mutational pathway at early stages, to lated state is accompanied by the Radiation, create a reducing environment that generation of potentially toxic by- oxygen shortage, Antioxidant enables tumour initiation. products, including ROS. Para carcinogens, ROS program DeNicola et al. also provide genetic doxically, however, whereas high in ammation support for their cell-based observations ROS levels are harmful to normal in a mouse model, elegantly showing that cells, they have long been thought DNA Nrf2 deficiency impairs the development to aid tumour development in several damage of K-Ras- and Braf-driven tumours. ways: by inducing DNA damage and so What’s more, early-stage cancer cells accelerating the rate of cancer-causing Senescence lacking Nrf2 had high ROS levels and evasion, mutations; by activating inflammatory ↑ proliferation exhibited a senescence-like growth arrest; pathways; and by stabilizing the hypoxia- Genomic but if they were treated with antioxidants, inducible factor — a key regulator of instability tumour proliferation resumed. energy metabolism4. These cancer- Nrf2 controls numerous stress- promoting actions of ROS underlie response genes beyond those mitigating the notion that use of antioxidants will oxidative stress; these include regulators reduce cancer risk. Cancer development of NADPH regeneration, heat-shock But there is another side to this coin: and progression proteins, drug-efflux pumps and various although many cancer cell types have growth factors7. It is therefore impor- increased levels of ROS, to avoid death tant to determine whether any of these even they must restrict their ROS ‘foot- Figure 1 | The right balance of reactive oxygen species alternative Nrf2 targets cooperate with print’ below a given threshold. Indeed, (ROS). Numerous intrinsic sources (such as certain activated the antioxidant response to facilitate tumours can use adaptive mechanisms oncogenes) and extrinsic factors (including radiation, oxygen tumorigenesis. Nevertheless, DeNicola to keep their ROS burden within a range shortage, carcinogens and inflammation) can give rise to ROS, and co-workers’ results suggest that permitting growth and survival5 — find- ultimately leading to ROS-mediated genomic instability and Nrf2-mediated adaptation to ROS stress ings that call for a more nuanced view of cancer. In addition, cancer cells may simultaneously switch is crucial for early stages of tumour the impact of ROS on tumorigenesis. on protective mechanisms to balance the deleterious effects of development, and if blocked may slow chronically high ROS levels. DeNicola et al.3, for example, show One such adaptive mechanism is that activation of the stress-response regulator NRF2 initiates a cancer progression. genetic targeting of the KEAP1–NRF2 pre-emptive antioxidant program that can counter ROS as well It is noteworthy that in previous studies, pathway in humans. Under normal con- as promote cell proliferation and survival. Tumour progression Nrf2-deficient mice showed increased, ditions, the repressor protein KEAP1 may therefore critically depend on the synergy between these rather than decreased, sensitivity to promotes NRF2 degradation. In response two pathways. the development of carcinogen-induced

7 JULY 2011 | VOL 475 | NATURE | 43 © 2011 Macmillan Publishers Limited. All rights reserved RESEARCH NEWS & VIEWS cancers6, and that exposure to antioxidants SATURN delayed tumorigenesis in several animal models4. Moreover, a number of oncogenic lesions — for instance, loss of the tumour- suppressor protein p53 — are associated with Storm-clouds brooding increased ROS levels, which seems to drive tumorigenesis8. These observations highlight the context-dependent roles of ROS in on towering heights cancer. Along these lines, an open question is Springtime on Saturn came in with a bang last December, when a massive whether the KEAP1–NRF2 pathway and other storm erupted in its north temperate zone. This rare event has been observed in active antioxidant processes also play a part unprecedented detail from the ground and from space. See Letters p.71 & p.75 during later stages of tumour development. In support of this idea, recent work9 indicates that growth of advanced pancreatic cancer PETER READ and professional) and those recording data requires ongoing autophagy — the process from NASA’s Cassini orbiter spacecraft, pre- whereby damaged organelles and proteins are aturn caught the attention of astronomers sent some of the most detailed observations degraded — in part to suppress accumulation in early December 2010 when a small, so far of such a dramatic event. These obser- of cytotoxic ROS levels. prominent white spot appeared in its nor- vations reveal with great clarity that the GWS So what is the broader significance of Smally bland and hazy northern hemisphere. comprises a massive complex of convective DeNicola and colleagues’ results3 for cancer During the ensuing days, this spot grew in size thunderstorms, upwelling heat energy and prevention and therapy? In particular, do they to a diameter approaching that of Earth and moisture from levels deep within Saturn’s imply that dietary antioxidants will increase developed a ‘tail’ of white clouds that spread atmosphere, accompanied by huge and almost the risk of cancer? The answer is probably no, eastwards until, two months later, it almost continuous lightning discharges. because the authors found that antioxidant encircled the entire planet. Just five similar Lightning discharges from convective supplementation has a positive effect on Great White Spot (GWS) events have been storms were observed5 on Jupiter by direct tumorigenesis only in the setting of genetic documented1,2 in the past 130 years. The events imaging on the planet’s nightside during the deletion of Nrf2 — a context unlikely to be recurred at intervals of roughly Saturn’s annual Voyager fly-bys in 1979. On Saturn, however, seen in human tumorigenesis. timescale of around 30 Earth years. What direct night-time imaging of lightning is not Additional studies are required to define seems to be different about this occurrence are usually possible6 because the lightning flashes whether such supplements can either increase the unexpectedly early timing of its appearance are too faint against the sunlight scattered from or decrease cancer risk depending on the (Saturn has only just begun its spring season the planet’s ring system. But pulses of radio presence of specific predisposing oncogenic in the northern hemisphere); its large size and emission, from events known as Saturn elec- lesions. As for the implications of these powerful intensity; and the unprecedented trostatic discharges (SEDs), have been detected findings3 for cancer treatment, they further observational resources available to measure from Saturn and attributed to thunderstorm highlight the potential for success of clinical and monitor its evolution. activity and lightning — for example7, from trials that aim to disable the protective anti- In two papers published in this issue3,4 the much smaller ‘dragon storm’ observed by oxidant pathway10, thus making cancer cells (pages 71 and 75), teams of observers, involv- Cassini in 2004. particularly vulnerable to death by oxidative ing both ground-based astronomers (amateur From the moment astronomers observed the stress. So far, there are very few treatment options for patients with either pancreatic or lung cancers. Identifying an Achilles heel for 250 Tropopause Cloud-top winds these tumours may provide an opportunity to 200 develop new treatments for these devastating 150 diseases. ■ 100

Altitude (km) 50 Rushika M. Perera and Nabeel Bardeesy are Cloudy tail 0 at the Massachusetts General Hospital, Cancer Center, and Department of Medicine, Harvard 0.15 0.5 Ammonia Medical School, Boston, Massachusetts 02114, ice clouds Deep winds USA. N 2 Convective W E e-mails: [email protected]; water clouds [email protected] S (bars) Pressure 10 1. Vafa, O. et al. Mol. Cell 9, 1031–1044 (2002). Movement of storm head 2. Irani, K. et al. Science 275, 1649–1652 (1997). with deep, westward ow 3. DeNicola, G. M. et al. Nature 475, 106–109 (2011). 4. Gao, P. et al. Cancer Cell 12, 230–238 (2007). 5. Gao, P. et al. Nature 458, 762–765 (2009). Figure 1 | Saturn’s great storm of 2010–11. The studies of Sánchez-Lavega et al.3 and Fischer et al.4 6. Kensler, T. W., Wakabayashi, N. & Biswal, S. Annu. indicate that the white clouds of this storm are produced by convective upwelling of heat, moisture Rev. Pharmacol. Toxicol. 47, 89–116 (2007). and ammonia from deep water clouds (originating at pressure levels of about 10 bars) into the upper 7. Hayes, J. D. & McMahon, M. Trends Biochem Sci. troposphere. As the upwelling material (green arrows) approaches the tropopause (where the temperature 34, 176–188 (2009). 8. Sablina, A. A. et al. Nature Med. 11, 1306–1313 stops decreasing with height and begins increasing into the stratosphere) at pressures of 0.1–0.5 bars, the (2005). bright, white, ammonia ice clouds spread horizontally (like ‘anvil’ thunderstorm clouds on Earth) and get 9. Yang, S. et al. Genes Dev. 25, 717–729 (2011). entrained into strong cloud-top eastward jets, producing an elongated ‘tail’, as visible in telescopic images of 10. Trachootham, D., Alexandre, J. & Huang, P. the storm. The cluster of convective clouds seems to move westward relative to the winds at the cloud tops, Nature Rev. Drug Discov. 8, 579–591 (2009). suggesting that westward zonal winds are stronger at deeper levels, where the convection is initiated.